EphB4, sometimes referred to as Ephrin Receptor B4 or Hepatoma Transmembrane Kinase (HTK), belongs to a family of transmembrane receptor protein-tyrosine kinases. EphB4 has an extracellular domain composed of the ligand-binding domain (also referred to as globular domain), a cysteine-rich domain, and a pair of fibronectin type III repeats (e.g., see FIG. 5). The cytoplasmic domain consists of a juxtamembrane region containing two conserved tyrosine residues; a protein tyrosine kinase domain; a sterile α-motif (SAM) and a PDZ-domain binding motif. EphB4 interacts with the membrane-bound ligand Ephrin B2 (Sakano, S. et al Oncogene. 1996 Aug. 15; 13(4):813-22; Brambilla R. et al EMBO J. 1995 Jul. 3; 14(13):3116-26). EphB4, like other members of the Eph family, is activated by binding of clustered, membrane-attached ephrin ligands (Davis S et al, Science. 1994 Nov. 4; 266(5186):816-9), indicating that contact between cells expressing the receptor and cells expressing the ligand is required for the Eph receptor activation. Upon ligand binding, an EphB4 receptor dimerizes and autophosphorylates the juxtamembrane tyrosine residues to acquire full activation. It has generally been thought that when an EphB4-expressing cell encounters an EphrinB2-expressing cell, the EphB4-EphrinB2 interaction and aggregation triggers signaling in both cells.
EphB4-EphrinB2 signaling has been implicated in angiogenesis (Wang et al. Cell. 1998 May 29; 93(5):741-53; Gerety et al. Mol. Cell. 1999 September; 4(3):403-14). Angiogenesis, the development of new blood vessels from the endothelium of a preexisting vasculature, is a critical process in the growth, progression, and metastasis of solid tumors within the host. During physiologically normal angiogenesis, the autocrine, paracrine, and amphicrine interactions of the vascular endothelium with its surrounding stromal components are tightly regulated both spatially and temporally. Additionally, the levels and activities of proangiogenic and angiostatic cytokines and growth factors are maintained in balance. In contrast, the pathological angiogenesis necessary for active tumor growth is sustained and persistent, representing a dysregulation of the normal angiogenic system. Solid and hematopoietic tumor types are particularly associated with a high level of abnormal angiogenesis.
It is generally thought that the development of a tumor consists of sequential, and interrelated steps that lead to the generation of an autonomous clone with aggressive growth potential. These steps include sustained growth and unlimited self-renewal. Cell populations in a tumor are generally characterized by growth signal self-sufficiency, decreased sensitivity to growth suppressive signals, and resistance to apoptosis. Genetic or cytogenetic events that initiate aberrant growth sustain cells in a prolonged “ready” state by preventing apoptosis.
It is a goal of the present disclosure to provide agents and therapeutic treatments for inhibiting angiogenesis and tumor growth.